Nanotherapies for the treatment of neurodevelopmental disorders.

用于治疗神经发育障碍的纳米疗法。

• 批准号: 8671529
• 负责人: Kannan Rangaramanujam
• 金额: $ 36.45万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8671529
• 关键词: Acetylcysteine; Adult; Affect; Age; Age-Months; Astrocytes; Autistic Disorder; Birth; Blood - brain barrier anatomy; Blood Circulation; Blood Circulation Time; Brain; Brain Injuries; Cells; Cerebral Palsy; Chemistry; Child; Childhood; Chronic; Clinical; Dendrimers; Development; Diffuse; Disease; Disulfides; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Economic Burden; Esters; Fluorescence; Generations; Goals; Human; Hydroxyl Radical; Immunohistochemistry; Inflammation; Injury; Life; Ligands; Link; Mannose; Mediating; Microglia; Modeling; Motor; Nanotechnology; Neonatal; Nervous System Physiology; Neurodevelopmental Disorder; Neuronal Injury; Newborn Infant; Organ; Oryctolagus cuniculus; Pathogenesis; Pathology; Perinatal; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Play; Positron-Emission Tomography; Prenatal Injuries; Proteins; Public Health; Research; Role; Safety; Surface; Technology; Testing; Therapeutic; Toxic effect; Translations; attenuation; base; cyanine dye 5; design; disability; improved; in vivo; innovation; interest; intravenous administration; mannose receptor; motor function improvement; myelination; nanoparticle; nanotherapeutic; nanotherapy; nervous system disorder; neuroinflammation; novel; novel therapeutic intervention; overexpression; postnatal; prenatal; public health relevance; receptor; social; uptake

Project Summary Neurodevelopmental disorders such as cerebral palsy (CP) and autism are chronic disabilities with no effective cure, resulting in significant personal, social and economic burden. Neuroinflammation, mediated by activated microglia and astrocytes, plays a key role in the pathogenesis of cerebral palsy (CP) and autism. Targeting activated microglia/astrocytes in the brain may offer such an opportunity. This is a challenge at multiple levels. Our preliminary studies suggest that, upon intravenous administration, poly(amidoamine) (PAMAM) dendrimers (~4 nm), cross the blood-brain barrier (BBB), and further accumulate selectively in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not in age-matched healthy controls. Importantly, a single 10 mg/kg drug dose in the form of this dendrimer-N-acetyl cysteine conjugate (D- NAC) administered on the day of birth (3 days after injury) intravenously to rabbit kits with CP, resulted in a significant improvement in motor function, attenuation of activated microglia, and decrease in neuronal injury and improved myelination by 5 days. Building on these promising findings, the long-term goal of this research is to develop dendrimer-based therapeutic approaches for the sustained postnatal treatment of neuroinflammation in CP. This will be achieved using the following specific aims: (1) determine whether increasing blood circulation time of dendrimers and using ligand targeting will improve microglial uptake and retention; (2) evaluate the toxicity of the dendrimer vehicle, and pharmacokinetics of NAC conjugated to dendrimers; (3) assess the sustained efficacy of the D- NAC conjugates, in improving motor function, decreasing microglial activation and brain injury up to 30 days. This study is significant because it: (1) explores the potential of targeted post-natal therapy in CP for improvement in motor phenotype, which has been a big challenge; (2) exploits the pathology-dependent differential uptake of PAMAM dendrimers by cells involved in neuroinflammation in CP; (3) will enable sustained attenuation of neuroinflammation during a crucial phase of brain development by providing tailored drug release; (4) uses NAC, a drug with a good safety profile in the perinatal and neonatal period, which can enable clinical translation. This study is innovative, because: (1) we evaluate therapeutic options in the postnatal period for a prenatal insult, to effect an improvement in motor function, with significant implications; (2) we seek to develop nanotherapeutic applications in the perinatal and neonatal period. Pediatric illnesses are often underserved by novel drug delivery technologies, which focus primarily on adults. This is the first study to bring nanotherapeutic approaches to childhood disorders such as CP.

项目摘要 神经发育障碍，例如脑瘫（CP）和自闭症是慢性残疾，没有 有效治愈，导致重大的个人，社会和经济负担。神经炎症，由 活化的小胶质细胞和星形胶质细胞在脑瘫（CP）和自闭症的发病机理中起关键作用。 靶向大脑中活化的小胶质细胞/星形胶质细胞可能会提供这样的机会。这是一个挑战 多个级别。我们的初步研究表明，在静脉内给药后，聚氨（amidoamine） （PAMAM）树枝状聚合物（〜4 nm），越过血脑屏障（BBB），然后选择性地积累 CP的新生兔子大脑中活化的小胶质细胞和星形胶质细胞，但没有年龄匹配的健康 控件。重要的一点 NAC）在出生当天（受伤后3天）静脉注射到具有CP的兔子试剂盒，导致 运动功能的显着改善，活化的小胶质细胞的衰减以及神经元损伤的减少 并改善了5天的髓鞘形成。 在这些有前途的发现的基础上，这项研究的长期目标是开发基于树枝状聚合物 CP中神经炎症后持续产后治疗的治疗方法。这将被实现 使用以下特定目的：（1）确定树枝状聚合物和树枝状循环时间是否增加 使用配体靶向将改善小胶质的摄取和保留率； （2）评估树突聚合物的毒性 NAC与树枝状聚合物共轭的车辆和药代动力学； （3）评估D-的持续功效 NAC结合物在改善运动功能时，将小胶质细胞激活和脑损伤降低了30天。 这项研究很重要，因为它是：（1）探讨针对CP中靶向产后治疗的潜力 运动表型的改善，这是一个巨大的挑战； （2）利用病理依赖性 CP中参与神经炎症的细胞对PAMAM树状聚合物的差异摄取； （3）将启用 在大脑发育的关键阶段，神经炎症的持续衰减通过提供量身定制 药物释放； （4）使用NAC，一种在围产期和新生儿时期具有良好安全性的药物，可以 启用临床翻译。这项研究具有创新性，因为：（1）我们评估了治疗选择 产后侮辱的产后时期，以改善运动功能，具有显着影响； （2）我们试图在围产期和新生儿时期开发纳米治疗应用。小儿疾病 通常由新型药物输送技术提供的服务不足，这些技术主要集中在成年人上。这是第一个 为CP等儿童疾病带来纳米治疗方法的研究。